Polycarbonate-polyurethane dispersions for thrombo-resistant coatings

ABSTRACT

A medical device is described which has on a surface thereof a bio-compatible coating. This bio-compatible coating is formed from a composition which includes an aqueous emulsion or dispersion of a polycarbonate-polyurethane composition containing one or more internal emulsifying agents.

FIELD OF INVENTION

[0001] This invention relates generally to medical devices havingbio-compatible substrate coatings. More particularly, the presentinvention relates to an implantable medical device or a part thereofwhich has a bio-compatible coating for enhancing the biostability of thedevice. Such a coating can also serve as a primer for a second coatinglayer which contains certain bio-active agents. Coatings and methods forincorporating such coatings onto the surface of medical devices are alsodescribed.

BACKGROUND OF THE INVENTION

[0002] It is generally known to provide a substrate, such as a medicaldevice or parts of such a device with various types of coatings forenhancing the biocompatability of the device when it is introduced intoa mammal, such as a human body.

[0003] In particular, implantable medical devices used for minimallyinvasive procedures in body conduits, such as for example in bloodvessels, the esophagus or urethra may be provided with bio-compatiblecoatings. Among the various intraluminal prostheses commonly used todayare vascular grafts which include endovascular grafts, stents andgraft-stent combinations. Various types of stents are available such aswire stents and tubular stents. These constructions may be made frommetals or polymers and may be of the balloon expandable type or theself-expanding type. Among the self-expanding type are those made fromsuperelastic, shape-memory materials such as nitinol. Other deviceswhich can benefit from such coatings include catheters, guide wires,trocars, introducer sheaths and the like.

[0004] Medical devices coated with bio-compatible coatings and methodsfor providing substrates with such coatings have been described in anumber of references, some of which are described below.

[0005] Various biocompatible coatings have been employed with medicaldevices in an attempt to impart enhanced bio-compatibility and otherproperties to such devices. For example, therapeutic agents have beenincorporated into polymeric films made from polyurethane, polyester,polylactic acid, polyamino acid, polyorthoester, polyphosphate ester andthe like, as disclosed in U.S. Pat. No. 5,282,823. U.S. Pat. No.5,163,958 discloses a stent having a binder layer and ananti-thrombogenic pyrolytic amorphous carbon layer attached to thebinder layer to provide an anti-thrombogenic surface.

[0006] Biologically active agents have been incorporated into polymericfilms for slow or controlled release of the active agent into the body.For example, U.S. Pat. No. 5,342,348 discloses porous polyurethane andPTFE stents having biodegradable polymeric filaments attached theretowhich release drug overtime. U.S. Pat. No. 5,383,928 discloses deliveryof a drug using a stent-sheath structure made from both degradable andnon-degradable polymers, such as ethylene vinyl acetate (EVA).

[0007] Endoprostheses have also been developed for targeted drugdelivery to sites within a body. Such endoprostheses can be coated withmicroporous materials having pores in which bio-active agents may beanchored for controlled delivery thereof over time. In particular, U.S.Pat. No. 5,449,382 to Dayton (hereinafter the “'382 patent”) discloses aminimally invasive bio-activated endoprosthesis for vessel repair. Thisendoprosthesis is coated with a polymer having a microporous structurewith a predetermined pore size and a bio-active substance disposedwithin these pores for elution therefrom. The coating described by the'382 patent is made from a polymeric solution which includes silicone,polyurethane, polyvinyl alcohol, polyethylene, biodegradable polylacticacid polymers, polyglycolic acid polymers, polyesters, hydrogels,tetrafluoroethylene, polytetrafluoroethylene, fluorosilicone etc.Admixed into one of these polymers is a bio-active agent, such as forexample heparin, for controlled and prolonged release thereof.

[0008] One drawback to conventional biocompatible coatings is the use oforganic solvents. Such organic solvents may be highly reactive in vivoif not completely removed prior to implantation. Furthermore, ininstances where the bio-active agent is admixed with the polymer, thesurface of the article coated with such a composition is not necessarilycontinuously bio-active, i.e., active throughout the entire surface.Thus, such a coating may be less effective at preventing, e.g.,thrombosis formation, than coatings which are designed to provideresistance to thrombosis throughout the surface.

[0009] Although polyurethane coatings have been employed asbiomaterials, they are known to suffer from stability problems and suchcoatings are quickly bio-degraded and or bio-eroded. Thus, attempts havebeen made to develop medical devices and polyurethane coatings thereforwhich contain compositions which are less susceptible to bio-degradationand bio-erosion.

[0010] In particular, U.S. Pat. No. 5,133,742 to Pinchuk (hereinafterthe “'742 patent”) discloses a prosthesis formed frompolycarbonate-urethane polymers. Such polycarbonate-urethanecompositions are bio-compatible and less susceptible to biodegradationand/or bio-erosion than simple polyurethane coatings. The '742 patentdescribes forming the polycarbonate-urethane polymer from the reactionof a polycarbonate diol, a diisocyanate and a chain extender in asuitable organic solvent. This polymer is then spun through aspinnerette into a filamentous vascular graft. Prostheses formedentirely from such a composition, however, are expensive to produce.

[0011] U.S. Pat. No. 5,575,818 to Pinchuk discloses a locking ring orbarb-type braided stent coated or lined with porous bio-compatiblecoating materials which include polyurethane, spun polyurethane, spunpolycarbonate urethane, spun polyolefin, silicone coated polyurethane,spun silicone and combinations thereof. This patent, however, suffersfrom the drawback, that most of the materials, including the spunpolycarbonate urethane coatings or linings are applied in anon-efficient, labor intensive manner. In particular, the preferredmethod for forming the liner or coating includes spinning the polymer ona mandrel at an angle coincident with the pitch angle of the stent(i.e., the pitch angle of the stent's body section, as well as, thelocking ring ends thereof). The lining is then applied to anadhesive-covered stent.

[0012] EP Publication No. 627 226 to Severini (hereinafter the “Severinipublication”) also describes a stent which is coated with apolycarbonate-urethane composition. This coating composition, however,suffers from the drawback that it is applied to the stent as a segmentedthermoplastic polycarbonate-urethane solution containing an organicsolvent, such as dimethylacetamide. A stent coated with such acomposition is clearly not desirable because of the danger to thepatient should all of the organic solvent not be evaporated prior toimplantation. Furthermore, the evaporation of organic solvents, such asdimethylacetamide, not only increases the health risks to manufacturingpersonnel but also pollutes the environment. Moreover, the requiredevaporation step adds a significant amount of time to the coatingprocess, i.e., 24 hours. Still further, in the Severini publication, theprocess of applying the polycarbonate-urethane coating to the stent isslow and inefficient. In particular, the process includes rotating thestent at a speed of 2 rpm while the coating is dripped onto the stentfrom a pipette suspended thereover. Coatings formed in such a manner areunequal and nonuniform.

[0013] The present invention is directed to aqueous dispersions oremulsions of polycarbonate-polyurethane coatings for implantable devicesand methods of preparation thereof. These coatings are particularlyadvantageous because they make it possible to impart implantable deviceswith long-term biostability and such coatings serve as superior primerlayers for attachment of optional bio-active agents. Furthermore, due tothe aqueous-based nature of the coatings of the present invention, theyare less hazardous than the prior art coatings cited hereinabove.Moreover, these coatings are highly versatile and can be efficientlyapplied to a wide range of substrates including heat sensitivesubstrates, such as, polyethyleneterphlate (PET) balloon catheters andstents. Because the optional bio-active agents of the present inventionare covalently bonded to the polycarbonate-polyurethane primer, thebio-active agents are permanently attached to the substrate unlikecertain of the transient coatings discussed above.

[0014] In summary, all of the references cited above suffer from thedrawback that they use organic solvents in their coating layer and/orcure at high temperatures. Thus, there is a need for improvedbio-compatible coatings which enhance the biostability,abrasion-resistance, lubricity and bio-activity of the surface ofimplantable medical devices, especially heat sensitive medical devicesand coatings which have heat-sensitive biomolecules. In particular,there is a need for improved, cost efficient compositions and deviceswhich have antithrombogenic properties and for more efficient methods ofproviding same. The present invention is directed to meeting these andother needs.

SUMMARY OF THE INVENTION

[0015] In one embodiment of the present invention there is provided amedical device having on a surface thereof a continuous bio-compatiblecoating. This bio-compatible coating is formed from an aqueous emulsionor dispersion of a polycarbonate-polyurethane composition containing oneor more internal emulsifying agents.

[0016] In another embodiment of the present invention, there is provideda process for rendering a medical device bio-compatible. This processincludes providing a substrate with a coating which contains an aqueousemulsion or dispersion of a polycarbonate-polyurethane compositionhaving at least one internal emulsifying agent. The coating is thendried onto the substrate to attach the coating to said substrate.

[0017] In a further embodiment of the present invention, there isprovided a coating for enhancing the bio-activity of a surface of amedical device. This coating is formed from an aqueous emulsion ordispersion which includes a polycarbonate-polyurethane compositioncontaining an organic acid functional group and an excess of apolyfunctional cross-linking agent. This composition forms a coating ona surface of the medical device and is reactive with thrombo-resistantagents.

[0018] In yet a further embodiment of the present invention, there isprovided a medical device with enhanced thrombo-resistance. This medicaldevice includes a substrate having a surface to which a continuousthrombo-resistant coating may be attached. The thrombo-resistant coatingcontains an aqueous emulsion or dispersion of apolycarbonate-polyurethane composition containing an internalemulsifying agent. This composition is attached to the substratesurface.

[0019] In another embodiment, a medical device is provided which has asurface which is rendered bio-compatible by means of a first coatinglayer. This coating layer includes a layer of apolycarbonate-polyurethane composition which contains an internalemulsifying agent.

[0020] In still a further embodiment, there is provided a medical devicewhich has a surface coated with a bio-active layer. This bio-activelayer is the reaction product of a polycarbonate-polyurethane firstlayer which contains an internal emulsifying agent and a polyfunctionalcross-linking agent and a bio-active agent second layer which has atleast one organic acid functional group.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention is directed to medical devices havingbio-compatible coatings attached to a surface thereof. Thesebio-compatible coatings are formed from an aqueous emulsion ordispersion of a polycarbonate-polyurethane composition containing one ormore internal emulsifying agents. Such coatings alone are sufficient toprovide a medical device with a bio-compatible surface. To augment sucha bio-compatible coating, a second coating layer may be applied over thepolycarbonate-polyurethane coating composition. When such augmentationis desired, it is preferred that the internal emulsifier in thepolycarbonate-polyurethane composition contain one or more organic acidfunctional groups or metal salts thereof. When such augmentation is notdesired, however, the internal emulsifying agent in thepolycarbonate-polyurethane composition can be any internal emulsifierknown in the art which is compatible with the intended use of thepresent invention.

[0022] For purposes of the present invention, the term “organic acidfunctional group” is meant to include any functional group whichcontains an organic acidic ionizable hydrogen. Examples of suchfunctional groups include free carboxylic, free sulfonic, and freephosphoric acid groups, their metal salts and combinations thereof. Suchmetal salts include, for example, alkali metal salts like lithium,sodium and potassium salts; alkaline earth metal salts like calcium ormagnesium salts; and quaternary amine salts of such acid groups,particularly quaternary ammonium salts.

[0023] In the present invention, the organic acid functionalgroup-containing polycarbonate-polyurethane composition is selectedbased on the nature of the substrate to be coated. Such compositions areaqueous based and provide enhanced biostability to the surface of amedical device over conventional polyurethane coatings. Furthermore,such compositions have increased bio-compatibility and areenvironmentally friendly because traditionally used organic solvents arenot required in order to apply the composition of the present inventionto the surface of a medical device. Moreover, because these compositionsare aqueous-based, they can be applied to a wide variety of substrateswithout concern for attack of a solvent on the substrate.

[0024] Polycarbonate-polyurethane aqueous dispersions and/or emulsionsuseful in the present invention include those which are commerciallyavailable from Zeneca Resins under the trade names NeoRez R-985(aliphatic polycarbonate diol) and NeoRez R-986 (aliphatic polycarbonatediol); from Industrial Copolymer Ltd. under the trade names W830/048(polycarbonate backbone), W830/092 (modified polycarbonate background),W830/140 (polycarbonate backbone) and W830/256 (polycarbonatebackground); and from Miles Inc. (Bayer AG) under the trade namesBayhydrol 121 (anionic dispersion of an aliphatic polycarbonate urethanepolymer in water and n-methyl-2-pyrrolidone with a tensile strength of6700 psi and an elongation at break of 150%) and Bayhydrol 123 (anionicdispersion of an aliphatic polycarbonate urethane polymer in water andn-methyl-2-pyrrolidone with a tensile strength of 6000 psi and anelongation at break of 320%).

[0025] In the present invention, the useful concentration of thepolycarbonate-polyurethane aqueous emulsion or dispersion is from about0.1% to about 60% by weight, and preferably from about 1% to about 20%by weight. These percent weight values are calculated based on theamount of solid polymer compared to the total weight of the firstcoating.

[0026] When it is desired to augment the firstpolycarbonate-polyurethane coating with a second coating containing abio-active agent, the polycarbonate-polyurethane aqueous emulsion ordispersion optionally includes one or more polyfunctional cross-linkingagents that are reactive with organic acid functional groups, includingthose functional groups functioning as internal emulsifiers on thepolycarbonate-polyurethane composition of the present invention. Variouspolyfunctional cross-linking agents may be used. In the presentinvention, preferred polyfunctional cross-linking agents includepolyfunctional aziridines and polyfunctional carbodiimides.

[0027] Furthermore, in the present invention, other cross-linking agentsmay also be used which include, for example, commercially availablepreparations sold by Zeneca Resins under the trade name NeoCryl CX 100and those preparations sold by EIT Industries under the trade nameXAMA-7. A commercially available polyfunctional carbodiimide which isalso useful in the present invention is Ucarlink XL-29SE, sold by UnionCarbide.

[0028] Among the polyfunctional aziridines particularly useful in thepresent invention are the trifunctional aziridines of the followingformula:

[0029] Preferably, the cross-linking agent has more than two functionalgroups per molecule. Furthermore, the present invention also encompassesa combination of different polyfunctional cross-linking agents.

[0030] Not wishing to be bound by a particular theory, it is believedthat the functional groups on the cross-linking agent serve at least twopurposes. In particular, these groups serve to cross-link thepolycarbonate-polyurethane composition when the internal emulsifiercontains an organic acid functional group. Additionally, these groups onthe cross-linking agent participate in covalently bonding a secondcoating composition containing a bio-active agent which has one or moreorganic acid functional groups to the polycarbonate-polyurethanecomposition through the excess organic acid functional groups on thepolyfunctional cross-linking agent. Thus, there must be sufficientfunctionality in the cross-linking agent, e.g. an excess ofcross-linking agent, to accomplish both purposes. In particular, theremust be a molar excess of cross-linking agent relative to thepolycarbonate-polyurethane composition to ensure that it issubstantially cross-linked, and that there are enough unreactedfunctional groups left on the cross-linking agent to covalently bond thebio-active agent to the polycarbonate-polyurethane composition.

[0031] One indication that insufficient functional groups from theoptional cross-linking agent are present is the inadequate bonding ofthe optional bio-active agent to the surface of the medical device. Thisis evidenced by the lack of bio-activity on the surface of medicaldevices treated with such a deficient polycarbonate-polyurethanecomposition.

[0032] The concentration of the optional cross-linking agent in thepolycarbonate-polyurethane composition is in the range from about 0.2%to about 30% by weight, and preferably in the range from about 0.5% toabout 20% by weight.

[0033] The aqueous polycarbonate-polyurethane composition may includeother conventional additives, such as for example, leveling agents,various stabilizers, pH adjustment agents, defoaming agents, thickeningagents, fillers, and the like, as long as, such agents are compatiblewith the intended use of the coated substrate.

[0034] The polycarbonate-polyurethane composition is applied to asubstrate, i.e., an implantable medical device, by conventional methods,including dipping and spraying. This composition is then dried to obtaina continuous, thrombo-resistant, substantially water-insoluble coatingon the surface of the medical device. Thus, thepolycarbonate-polyurethane composition alone is able to effectivelyfunction as a thrombo-resistant top coat for implantable medicaldevices. As set forth above, when the polycarbonate-polyurethanecomposition is used alone, any internal emulsifying agent may be usedwhich is compatible with the intended medical uses of the presentinvention. The selection of such internal emulsifying agents is wellwithin the knowledge of one skilled in the art.

[0035] If, however, it is desired to modify and/or augment the finalproperties of an implantable medical device coated with the presentpolycarbonate-polyurethane top coat, it is a simple matter to modifythis composition to function as a binder for a second coating layerwhich contains a bio-active agent as described in more detail below. Inparticular, when a bio-active agent coating is to be applied over thepolycarbonate-polyurethane coating, the internal emulsifying agent mustcontain at least one organic acid functional group or similarfunctioning moiety. A polyfunctional cross-linking agent as describedabove is then added to the polycarbonate-polyurethane coatingcomposition.

[0036] This modified polycarbonate-polyurethane aqueous emulsion ordispersion includes a cross-linking agent which has functional groupswhich are reactive with the internal emulsifying agent's organic acidgroups. This modified coating composition is then applied to a surfaceof the implantable medical device and dried as described below. Theimplantable medical device is then contacted with an aqueous solution ordispersion of an organic acid functional group-containing bio-activeagent. This solution is applied over the polycarbonate-polyurethane topcoat in the same or a different manner as the polycarbonate-polyurethanecoating was applied to the substrate. The bio-active coating is thenpermitted to dry, thereby covalently bonding the organic acid functionalgroup-containing bio-active agent to the polycarbonate-polyurethane topcoat via the excess, unreacted functional groups of the cross-linkingagent.

[0037] Bio-active agents for use in bio-compatible coatings includethose known in the art. In the present invention, any bio-active agentmay be used in the second coating provided that it contains at least oneorganic acid functional group in its structure which can react with thepolyfunctional cross-linking agent and still retain its bio-activefunction.

[0038] The bio-active agent of the present invention may include, forexample, thrombo-resistant agents, antibiotic agents, anti-tumor agents,antiviral agents, anti-angiogenic agents, angiogenic agents,anti-mitotic agents, anti-inflammatory agents, angiostatin agents,endostatin agents, cell cycle regulating agents, genetic agents,including hormones such as estrogen, their homologs, derivatives,fragments, pharmaceutical salts and combinations thereof. Other usefulbio-active agents include, for example, viral vectors and growthhormones such as Fibroblast Growth Factor and Transforming GrowthFactor-β.

[0039] Furthermore, the bio-active agent of the present invention caninclude organic acid functional group-containing thrombo-resistantagents. For purposes of the present invention, such thrombo-resistantagents include heparin, heparin sulfate, hirudin, hyaluronic acid,chondroitin sulfate, dermatan sulfate, keratin sulfate, lytic agents,including urokinase and streptokinase their homologs, analogs,fragments, derivatives and pharmaceutical salts thereof.

[0040] Moreover, the bio-active agent of the present invention can alsoinclude organic acid functional group-containing antibiotics. Forpurposes of the present invention, such antibiotics include penicillins,cephalosporins, vancomycins, aminoglycosides, quinolones, polymyxins,erythromycins, tetracyclines, chloramphenicols, clindamycins,lincomycins, sulfonamides their homologs, analogs, fragments,derivatives, pharmaceutical salts and mixtures thereof.

[0041] Additionally, the bio-active agent of the present invention canalso include organic acid functional group-containing anti-tumor agents.For purposes of the present invention, such anti-tumor agents includepaclitaxel, docetaxel, alkylating agents including mechlorethamine,chlorambucil, cyclophosphamide, melphalan and ifosfamide;antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouraciland cytarabine; plant alkaloids including vinblastine, vincristine andetoposide; antibiotics including doxorubicin, daunomycin, bleomycin, andmitomycin; nitrosureas including carmustine and lomustine; inorganicions including cisplatin; biological response modifiers includinginterferon; enzymes including asparaginase; and hormones includingtamoxifen and flutamide their homologs, analogs, fragments, derivatives,pharmaceutical salts and mixtures thereof.

[0042] Still further, the bio-active agent of the present invention caninclude organic acid functional group-containing anti-viral agents. Forpurposes of the present invention, such anti-viral agents includeamantadines, rimantadines, ribavirins, idoxuridines, vidarabines,trifluridines, acyclovirs, ganciclovirs, zidovudines, foscarnets,interferons their homologs, analogs, fragments, derivatives,pharmaceutical salts and mixtures thereof.

[0043] In certain cases, such bio-active agents may also becomelubricous upon contact with an aqueous medium. Such lubricity willdepend on a number of factors, including the type of bio-active agent,its molecular weight, the exposure level to the aqueous medium, as wellas, the presence of agents which facilitate wetting. In the presentinvention, the molecular weight of the bio-active agent can vary from,for example, about 3,000 to about 30,000 for heparin to an excess of8,000,000 for hyaluronic acid.

[0044] The concentration of the bio-active agent will vary dependingupon the particular agent used, its intended function and the chosensubstrate. It is within the knowledge of one skilled in the art, knowingthe above-referenced variables, to calculate appropriate bio-activeagent concentrations for use in accordance with the present invention.

[0045] As set forth above, when used as a thrombo-resistant top coat foran implantable medical device, the polycarbonate-polyurethanecomposition is applied to a surface thereof and permitted to dry at atemperature below 120° C. Preferably, this drying takes place betweenabout 10° C. to about 70° C. More preferably, this top coat is dried atambient or room temperatures, such as for example, at or between about15° C. and about 35° C.

[0046] The drying step for the optional second coating as describedabove is chosen based on the composition of the medical device, thepolycarbonate-polyurethane composition and the bio-active agent. Theselection of the appropriate drying temperature is within the skill ofthe art given the properties of the substrate and the compositional makeup of the polycarbonate-polyurethane and bio-active agent coatings.Preferably, the drying steps take place well below 120° C. If desired,however, and compatible with the nature of the medical device to becoated, higher temperatures may be used, such as for example, when thesubstrate is metal.

[0047] Nevertheless, the present invention is particularly intended tobe used to coat temperature-sensitive substrates using temperaturesensitive bio-active agents. Thus, the optional bio-active agent, aswell as the polycarbonate-polyurethane top coat are preferably dried atlow temperatures, particularly at ambient or room temperatures, such asfor example, at or between about 15° C. and about 35° C. In many cases,drying at about room temperature for about 12 hours will be adequate.Surface coatings formed in such a manner are long lasting, highlybio-active, anti-abrasive and, depending upon the bio-active agent used,may also be highly lubricious.

[0048] Obviously, the drying time will depend on the drying temperatureused, higher drying temperatures requiring shorter drying times andlower drying temperatures requiring longer drying times. As set forthabove, it is within the knowledge of a person skilled in the art todetermine a suitable combination of drying temperatures and drying timesfor a specific coating and substrate.

[0049] Furthermore, the organic acid functional groups of thecross-linking agent do not necessarily have to have the same reactivitytowards the organic acid functional groups of thepolycarbonate-polyurethane composition and the bio-active agents,respectively. Moreover, the selection of drying conditions will be madewith these reactivities in mind.

[0050] Still further, in the present invention, multiple layers of thepolycarbonate-polyurethane coating, either alone or in combination withmultiple layers of the bio-active agent coatings may be applied to thesurface of an implantable medical device. It is within the skill of theart to determine appropriate drying times when multiple coatings areapplied to an implantable medical device.

[0051] For purposes of the present invention, the term “medical device”or “medical devices” includes implantable medical devices, includingendoprosthetic devices. Such devices include, for example, vascular andnonvascular stents, grafts and stent-graft combinations. Also includedin the present invention are catheters and guide wires. Nonvascularstents encompassed by the present invention include, for example,esophageal stents, urinary stents, biliary stents, and colonic stents.Stents useful in the present invention include those which are balloonexpandable and self-expanding. Superelastic, shaped memory materials,such a nitinol, are among those materials useful for the self-expandingtype of stents.

[0052] The medical device of the present invention is made from anymaterial which is suitable for implantation into the body of a mammal,such as a human, and to which the present bio-compatible coatingcompositions can bind. In particular, the present device can be apolymer, a non-polymer or mixtures thereof. Furthermore, the medicaldevice of the present invention may include a combination of one or morepolymers and/or one or more non-polymers.

[0053] The types of polymers which can be used to manufacture thepresent medical devices are quite diverse. Such polymers include bothdegradable and non-degradable polymers. The medical device of thepresent invention is made from, for example, non-degradable polymercompositions, such as, olefin polymers including polyethylene,polypropylene, polyvinyl chloride, polytetrafluoroethylene, polyvinylacetate, polystyrene, poly(ethylene terephthalate), polyurethane,polyurea, silicone rubbers, polyamides, polycarbonates, polyaldehydes,natural rubbers, polyether-ester copolymers, styrene-butadienecopolymers and combinations thereof.

[0054] As set forth above, the medical device of the present inventioncan also be made from degradable polymer compositions includingpolysaccharides such as for example, methyl cellulose, hydroxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxpropylethyl cellulose, sodiumcarboxymethyl cellulose, hyaluronic acid, chondroitin sulfate, chitosan,dextran, xanthan, gellan, alginic acid, jota carrageenan; polypeptidessuch as for example, collagen, gelatin, elastin, albumin; and syntheticpolymers such as for example, poly(vinyl alcohol), poly(lactic acid),polyglycolic acid, poly-ε-caprolactone, polyanhydride their copolymersand mixtures thereof.

[0055] As set forth above, the medical device of the present inventioncan also be made from non-polymer compositions. Such compositionsinclude, for example, ceramics, metals, glasses and combinationsthereof. When the medical device is made from a metal, a variety ofbiocompatible metals may be utilized such as for example, stainlesssteel, nitinol, tantalum, titanium, gold, silver, their alloys andmixtures thereof.

[0056] In another embodiment of the present invention, there is provideda process for rendering a medical device bio-compatible. This processincludes providing a substrate with a continuous surface coating of anaqueous emulsion or dispersion of a polycarbonate-polyurethanecomposition having at least one internal emulsifying agent, aspreviously described. The polycarbonate-polyurethane composition is thenpermitted to dry onto the substrate as previously described. Substratestreated in such a manner are provided with enhanced thrombo-resistanceover the entire coated surface area.

[0057] When it is desired to add a bio-active agent coating on top ofthe polycarbonate-polyurethane top coat, the polycarbonate-polyurethanetop coat is modified by selecting an internal emulsifying agent whichcontains at least one organic acid functional group. An excess of apolyfunctional cross-linking agent which is reactive with these organicacid functional groups is then added to the aqueouspolycarbonate-polyurethane emulsion or dispersion. Thus, to enhance,augment or modify the anti-thrombogenic nature of a substrate coated asdescribed above, a bio-active agent as previously described canoptionally be attached to the substrate via the excess polyfunctionalcross-linking agent. In particular, the polycarbonate-polyurethanecoated substrate is further contacted with a bio-active agent to form acontinuous coating thereon. The bio-active agent is then dried asdescribed previously to bond covalently the bio-active agent to thepolycarbonate-polyurethane composition via the excess polyfunctionalcross-linking agent. Thus, in this embodiment, thepolycarbonate-polyurethane coating composition functions as an effectiveundercoat or primer to which the bio-active agent is applied.

[0058] In another embodiment of the present invention, there is provideda coating for enhancing the bio-activity of a surface of a medicaldevice. The coating is formed from an aqueous emulsion or dispersion ofa polycarbonate-polyurethane composition having an organic acidfunctional group and an excess of a polyfunctional cross-linking agentas previously described. As set forth above, this composition isattached to the surface of the medical device and is reactive withbio-active agents also as described previously.

[0059] In yet a further embodiment of the present invention, a medicaldevice is provided with enhanced thrombo-resistance. This medical deviceincludes a substrate as described previously which has athrombo-resistant coating attached thereto. As set forth above, thisthrombo-resistant coating is attached to the substrate surface andcontains an aqueous emulsion or dispersion of apolycarbonate-polyurethane composition having an internal emulsifyingagent. This polycarbonate-polyurethane composition is prepared, forexample, by reacting a polyfunctional isocyanate with a polycarbonatediol. As set forth above, such compositions are normally obtained fromcommercial sources.

[0060] In yet another embodiment of the present invention, a medicaldevice is provided which has a surface rendered bio-compatible by meansof a first coating layer as previously described. This first coatinglayer includes a polycarbonate-polyurethane composition containing aninternal emulsifying agent. When it is desired to use thepolycarbonate-polyurethane composition as a top coat for a bio-activeagent coating, the internal emulsifying agent is selected to have atleast one organic acid functional group. This composition may alsoinclude a polyfunctional cross-linking agent.

[0061] As set forth above, a second coating layer may also be applied tothe above-referenced medical device. In particular, the second coatinglayer includes a bio-active agent covalently bonded to the first coatinglayer. The second coating layer is formed by the process which has beendescribed previously.

[0062] In still a further embodiment, a medical device is provided whichhas a surface coated with a bio-active layer. This bio-active layer isthe reaction product of a polycarbonate-polyurethane first layer asdescribed above which includes a polyfunctional cross-linking agent anda bio-active agent also as previously described.

[0063] The invention will now be further illustrated in the followingnon-limiting examples representing presently preferred embodiments ofthe invention.

EXAMPLE 1

[0064] An aqueous dispersion or emulsion is prepared by adding thefollowing ingredients successively to a glass beaker under properagitation until thoroughly mixed. NeoRez R985: 250 ml Water: 250 ml 0.5%Fluorad FC-129 stock solution:  10 ml (prepared by diluting 1 ml FluoradFC-129 in 100 ml of water) 34% NH₄OH:  4 ml

[0065] An implantable medical device is dipped into this aqueousdispersion and then withdrawn. Excess amounts of the aqueous compositionare allowed to drip off and the coated stent is then dried at roomtemperature for 12 hours. The coated implantable medical device exhibitssuperior thrombo-resistance when placed within the body of a mammal.

EXAMPLE 2

[0066] An aqueous dispersion or emulsion is prepared by adding thefollowing ingredients successively to a glass beaker under properagitation until thoroughly mixed. NeoRez R985: 250 ml Water: 250 ml 0.5%Fluorad FC-129 stock solution:  10 ml (prepared by diluting 1 ml FluoradFC-129 in 100 ml of water) 34% NH₄OH:  4 ml NeoCryl CX 100:  20 ml

[0067] An implantable medical device is dipped into this aqueousdispersion and then withdrawn. Excess amounts of the aqueous compositionare allowed to drip off and the coated device is then dried at roomtemperature for 12 hours.

[0068] A bio-active coating composition is prepared as follows: 1.2%aqueous solution of Heparin: 400 ml

[0069] This aqueous bio-active composition is prepared by adding anappropriate amount of heparin powder to water under agitation forseveral hours to obtain a clear homogeneous solution.

[0070] The medical device is dipped in the polycarbonate-polyurethanesolution and then air dried for 10 minutes. Immediately thereafter, thepolycarbonate-polyurethane coated implantable medical device is thendipped into the aqueous heparin solution and then withdrawn. Excessamounts of the aqueous bio-active composition are allowed to drip offand the coated stent is then air dried for 10 minutes. The coatedimplantable medical device exhibits superior thrombo-resistantproperties when placed within the body of a mammal.

EXAMPLE 3

[0071] The implantable medical device of EXAMPLE 2 is prepared with theexception that an antibiotic agent is substituted for the heparin. Thecoated implantable medical device exhibits superior anti-bioticproperties when placed within the body of a mammal.

EXAMPLE 4

[0072] The implantable medical device of EXAMPLE 2 is prepared with theexception that an antitumor agent is substituted for the heparin. Thecoated implantable medical device exhibits superior antitumor propertieswhen placed within the body of a mammal.

EXAMPLE 5

[0073] The implantable medical device of EXAMPLE 2 is prepared with theexception that an antiviral agent is substituted for the heparin. Thecoated implantable medical device exhibits superior antiviral propertieswhen placed within the body of a mammal.

EXAMPLE 6

[0074] The implantable medical device of EXAMPLE 2 is prepared with theexception that an anti-angiogenic agent is substituted for the heparin.The coated implantable medical device exhibits superior anti-angiogenicproperties when placed within the body of a mammal.

EXAMPLE 7

[0075] The implantable medical device of EXAMPLE 2 is prepared with theexception that an angiogenic agent is substituted for the heparin. Thecoated implantable medical device exhibits superior angiogenicproperties when placed within the body of a mammal.

EXAMPLE 8

[0076] The implantable medical device of EXAMPLE 2 is prepared with theexception that an anti-inflammatory agent is substituted for theheparin. The coated implantable medical device exhibits superioranti-inflammatory properties when placed within the body of a mammal.

EXAMPLE 9

[0077] The implantable medical device of EXAMPLE 2 is prepared with theexception that a cell cycle regulating agent is substituted for theheparin. The coated implantable medical device exhibits superior cellcycle regulating properties when placed within the body of a mammal.

[0078] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention and, all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A medical device having on a surface thereof abio-compatible coating, said bio-compatible coating formed from acomposition comprising an aqueous emulsion or dispersion of apolycarbonate-polyurethane composition containing one or more internalemulsifying agents.
 2. The medical device of claim 1, wherein said oneor more internal emulsifying agents comprise one or more organic acidfunctional groups selected from the group consisting of free carboxylicacid, free sulfonic acid, free phosphoric acid and combinations thereof.3. The medical device of claim 2, wherein said bio-compatible coatingfurther comprises an excess of a polyfunctional cross-linking agentwhich is reactive with said one or more organic acid functional groupson said polycarbonate-polyurethane composition.
 4. The medical device ofclaim 3, wherein said polyfunctional cross-linking agent is selectedfrom the group consisting of polyfunctional aziridines, polyfunctionalcarbodiimides and mixtures thereof.
 5. The medical device of claim 4,wherein said bio-compatible coating further contains a second coatingcomposition which comprises a bio-active agent having one or moreorganic acid functional groups which are covalently reactive with saidexcess polyfunctional cross-linking agent.
 6. The medical device ofclaim 5, wherein said bio-active agent is selected from the groupconsisting of thrombo-resistant agents, antibiotic agents, anti-tumoragents, growth hormones, antiviral agents, anti-angiogenic agents,angiogenic agents, anti-mitotic agents, anti-inflammatory agents, cellcycle regulating agents, genetic agents, hormones, their homologs,derivatives, fragments, pharmaceutical salts and combinations thereof.7. The medical device of claim 6, wherein said bio-active agent isselected from the group of thrombo-resistant agents consisting ofheparin, heparin sulfate, hirudin, hyaluronic acid, chondroitin sulfate,dermatan sulfate, keratan sulfate, lytic agents, including urokinase andstreptokinase their homologs, analogs, fragments, derivatives andpharmaceutical salts thereof.
 8. The medical device of claim 6, whereinsaid bio-active agent is selected from the group of antibiotic agentsconsisting of penicillins, cephalosporins, vancomycins, aminoglycosides,quinolones, polymyxins, erythromycins, tetracyclines, chloramphenicols,clindamycins, lincomycins, sulfonamides their homologs, analogs,derivatives, pharmaceutical salts and mixtures thereof.
 9. The medicaldevice of claim 6, wherein said bio-active agent is selected from thegroup of anti-tumor agents consisting of paclitaxel, docetaxel,alkylating agents including mechlorethamine, chlorambucil,cyclophosphamide, melphalan and ifosfamide; antimetabolites includingmethotrexate, 6-mercaptopurine, 5-fluorouracil and cytarabine; plantalkaloids including vinblastine, vincristine and etoposide; antibioticsincluding doxorubicin, daunomycin, bleomycin, and mitomycin; nitrosureasincluding carmustine and lomustine; inorganic ions including cisplatin;biological response modifiers including interferon; angiostatin agentsand endostatin agents; enzymes including asparaginase; and hormonesincluding tamoxifen and flutamide their homologs, analogs, fragments,derivatives, pharmaceutical salts and mixtures thereof.
 10. The medicaldevice of claim 6, wherein said bio-active agent is selected from thegroup of anti-viral agents consisting of amantadines, rimantadines,ribavirins, idoxuridines, vidarabines, trifluridines, acyclovirs,ganciclovirs, zidovudines, foscarnets, interferons their homologs,analogs, fragments, derivatives, pharmaceutical salts and mixturesthereof.
 11. The medical device of claim 1, wherein the concentration ofsaid aqueous emulsion or dispersion is from about 1% to about 50% byweight solids content.
 12. The medical device of claim 1, wherein saidsubstrate is a polymer, a non-polymer and combinations thereof.
 13. Themedical device of claim 12, wherein said polymer is selected from thegroup consisting of degradable polymers, non-degradable polymers andmixtures thereof.
 14. The medical device of claim 13, wherein saidsubstrate is further selected from the group of polymer compositionsconsisting of olefin polymers including polyethylene, polypropylene,polyvinyl chloride, polytetrafluoroethylene, polyvinyl acetate,polystyrene, poly(ethylene terephthalate), polyurethane, polyurea,silicone rubbers, polyamides, polycarbonates, polyaldehydes, naturalrubbers, polyether-ester copolymers, styrene-butadiene copolymers andcombinations thereof.
 15. The medical device of claim 13, wherein saidsubstrate is further selected from the group of polymer compositionsconsisting of polysaccharides such as for example, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxpropylethyl cellulose,sodium carboxymethyl cellulose, hyaluronic acid, chondroitin sulfate,chitosan, dextran, xanthan, gellan, alginic acid, jota carrageenan;polypeptides such as for example, collagen, gelatin, elastin, albumin;and synthetic polymers such as for example, poly(vinyl alcohol),poly(lactic acid), polyglycolic acid, poly-ε-caprolactone, polyanhydridetheir copolymers and mixtures thereof.
 16. The medical device of claim12, wherein said substrate is further selected from the group ofnon-polymer compositions consisting of ceramics, metals, glasses andcombinations thereof.
 17. The medical device of claim 16, wherein saidsubstrate is further selected from the group of metals consisting ofstainless steel, nitinol, tantalum, titanium, gold, silver, their alloysand mixtures thereof.
 18. The medical device of claim 1, wherein saidsubstrate is an implantable device.
 19. The medical device of claim 18,wherein said implantable device is selected from the group consisting ofgrafts, stents, graft-stent combinations and catheters.
 20. The medicaldevice of claim 19, wherein said stents are selected from the groupconsisting of vascular and nonvascular stents.
 21. The medical device ofclaim 20, wherein said nonvascular stents are selected from the groupconsisting of esophageal, urinary, biliary and colonic stents.
 22. Aprocess for rendering a medical device bio-compatible comprising: a)providing a substrate with a coating comprising an aqueous emulsion ordispersion of a polycarbonate-polyurethane composition having at leastone internal emulsifying agent; and b) drying said coating onto saidsubstrate to attach said coating to said substrate.
 23. The process ofclaim 22, wherein said at least one internal emulsifier is at least oneorganic acid functional group.
 24. The process of claim 23, wherein saidcoating further comprises an excess of a polyfunctional cross-linkingagent which is reactive with said at least one organic acid functionalgroup on said polycarbonate-polyurethane composition.
 25. The process ofclaim 24, further comprising the steps of: a. contacting said substratehaving said dried coating thereon with a bio-active agent, and b.forming a continuous bio-active coating on a surface of said substrateby drying said bio-active agent to covalently bond said bio-active agentto said coating via said excess polyfunctional cross-linking agent. 26.A coating for enhancing the bio-activity of a surface of a medicaldevice, said coating formed from an aqueous emulsion or dispersioncomprising a polycarbonate-polyurethane composition containing anorganic acid functional group and an excess of a polyfunctionalcross-linking agent, said composition forming a coating on a surface ofsaid medical device and being bonded thereto and reactive withbio-active agents.
 27. A medical device with enhanced thrombo-resistancecomprising: a) a substrate having a surface to which a continuousthrombo-resistant coating may be attached; and b) a thrombo-resistantcoating that contains an aqueous emulsion or dispersion of apolycarbonate-polyurethane composition containing an internalemulsifying agent, said composition being attached to said substratesurface.
 28. The medical device of claim 27, wherein saidpolycarbonate-polyurethane composition is prepared by reacting apolyfunctional isocyanate with a polycarbonate diol.
 29. A medicaldevice having a surface rendered bio-compatible by means of a firstcoating layer, said first coating layer comprising apolycarbonate-polyurethane composition containing an internalemulsifying agent.
 30. The device of claim 29, wherein said internalemulsifying agent includes at least one organic acid functional group.31. The device of claim 30, wherein said composition further comprises apolyfunctional cross-linking agent.
 32. The device of claim 31 furthercomprising a second coating layer of a bio-active agent covalentlybonded to said first coating layer, said second coating formed by theprocess of a) drying said first coating layer to said medical device; b)applying an aqueous emulsion or dispersion of said bio-active agenthaving at least one organic acid functional group onto said dried firstlayer; c) drying said first and second layers to covalently bond saidfirst layer to said second layer via said organic acid functional groupon said second layer and said multifunctional cross-linking agent.
 33. Amedical device having a surface coated with a bio-active layercomprising the reaction product of a polycarbonate-polyurethane firstlayer containing an internal emulsifying agent and a polyfunctionalcross-linking agent and a bio-active agent second layer having at leastone organic acid functional group.